Methods and apparatus for thermally-induced renal neuromodulation

ABSTRACT

Methods and apparatus are provided for thermally-induced renal neuromodulation. Thermally-induced renal neuromodulation may be achieved via direct and/or via indirect application of thermal energy to heat or cool neural fibers that contribute to renal function, or of vascular structures that feed or perfuse the neural fibers. In some embodiments, parameters of the neural fibers, of non-target tissue, or of the thermal energy delivery element, may be monitored via one or more sensors for controlling the thermally-induced neuromodulation. In some embodiments, protective elements may be provided to reduce a degree of thermal damage induced in the non-target tissues. In some embodiments, thermally-induced renal neuromodulation is achieved via delivery of a pulsed thermal therapy.

REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 11/599,723, filed Nov. 14, 2006, which claims the benefit ofU.S. Provisional Application No. 60/816,999 filed on Jun. 28, 2006. U.S.patent application Ser. No. 11/599,723, filed Nov. 14, 2006, is also acontinuation-in-part application of U.S. patent application Ser. No.10/408,665, filed on Apr. 8, 2003, now U.S. Pat. No. 7,162,303, whichclaims the benefit of U.S. Provisional Application Nos. (a) 60/370,190,filed on Apr. 8, 2002, (b) 60/415,575, filed on Oct. 3, 2002, and (c)60/442,970, filed on Jan. 29, 2003. Furthermore, U.S. patent applicationSer. No. 11/599,723, filed Nov. 14, 2006, is a continuation-in-partapplication of co-pending U.S. patent application Ser. No. 11/189,563,filed on Jul. 25, 2005, which is a continuation-in-part application ofU.S. patent application Ser. No. 11/129,765, filed on May 13, 2005, nowU.S. Pat. No. 7,653,665, and which claims the benefit of U.S.Provisional Application Nos. (a) 60/616,254, filed on Oct. 5, 2004, and(b) 60/624,793, filed on Nov. 2, 2004. Further still, U.S. patentapplication Ser. No. 11/599,723, filed Nov. 14, 2006, is acontinuation-in-part application of U.S. patent application Ser. No.11/504,117, filed on Aug. 14, 2006, now U.S. Pat. No. 7,617,005.

All of these applications are incorporated herein by reference in theirentireties.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

TECHNICAL FIELD

The present invention relates to methods and apparatus forneuromodulation. More particularly, the present invention relates tomethods and apparatus for achieving renal neuromodulation via thermalheating and/or cooling mechanisms.

BACKGROUND

Heart Failure or Chronic Heart Failure (“CHF”) is a condition thatoccurs when the heart becomes damaged and reduces blood flow to theorgans of the body. If blood flow decreases sufficiently, kidneyfunction becomes altered, which results in fluid retention, abnormalhormone secretions and increased constriction of blood vessels. Theseresults increase the workload of the heart and further decrease thecapacity of the heart to pump blood through the kidneys and circulatorysystem.

It is believed that progressively decreasing perfusion of the kidneys isa principal non-cardiac cause perpetuating the downward spiral of CHF.Moreover, the fluid overload and associated clinical symptoms resultingfrom these physiologic changes result in additional hospital admissions,poor quality of life and additional costs to the health care system.

In addition to their role in the progression of CHF, the kidneys play asignificant role in the progression of Renal Failure or Chronic RenalFailure (“CRF”), Renal Disease or End-Stage Renal Disease (“ESRD”),Hypertension (pathologically high blood pressure) and other cardio-renaldiseases. The functions of the kidneys can be summarized under threebroad categories: filtering blood and excreting waste products generatedby the body's metabolism; regulating salt, water, electrolyte andacid-base balance; and secreting hormones to maintain vital organ bloodflow. Without properly functioning kidneys, a patient will suffer waterretention, reduced urine flow and an accumulation of waste toxins in theblood and body. These conditions result from reduced renal function orrenal failure (kidney failure) and are believed to increase the workloadof the heart. In a CHF patient, renal failure will cause the heart tofurther deteriorate as fluids are retained and blood toxins accumulatedue to the poorly functioning kidneys.

It has been established in animal models that the heart failurecondition results in abnormally high sympathetic activation of thekidneys. An increase in renal sympathetic nerve activity leads todecreased removal of water and sodium from the body, as well asincreased renin secretion. Increased renin secretion leads tovasoconstriction of blood vessels supplying the kidneys, which causesdecreased renal blood flow. Reduction of sympathetic renal nerveactivity, e.g., via denervation, may reverse these processes.

Applicants have described methods and apparatus for treating renaldisorders by applying a pulsed electric field, preferably non-thermal,to neural fibers that contribute to renal function. See, for example,Applicants' co-pending U.S. patent application Ser. Nos. (a) 11/129,765,filed on May 13, 2005, (b) 11/189,563, filed on Jul. 25, 2005, and (c)11/363,867, filed Feb. 27, 2006, all of which are incorporated herein byreference in their entireties. A pulsed electric field (“PEF”) mayinitiate renal denervation or other neuromodulation via irreversibleelectroporation or other processes. The PEF may be delivered fromapparatus positioned intravascularly, extravascularly,intra-to-extravascularly or a combination thereof. Additional methodsand apparatus for achieving renal neuromodulation via localized drugdelivery (such as by a drug pump or infusion catheter) or use of astimulation electric field are described in co-owned and co-pending U.S.patent application Ser. No. 10/408,665, filed Apr. 8, 2003, and U.S.Pat. No. 6,978,174, both of which are incorporated herein by referencein their entireties.

A potential challenge of using non-thermal PEF systems for treatingrenal disorders is to selectively electroporate target cells withoutaffecting other cells. For example, it may be desirable to irreversiblyelectroporate renal nerve cells that travel along or in proximity torenal vasculature, but it may not be desirable to damage the smoothmuscle cells of which the vasculature is composed. As a result, anoverly aggressive course of non-thermal PEF therapy may persistentlyinjure the renal vasculature, but an overly conservative course ofnon-thermal PEF therapy may not achieve the desired renalneuromodulation.

Applicants have previously described methods and apparatus formonitoring changes in tissue impedance or conductivity in order todetermine the effects of pulsed electric field therapy. Such changes intissue can be used to determine an extent of electroporation and/or itsdegree of irreversibility in target or non-target tissue. See, forexample, Applicant's co-pending U.S. patent application Ser. No.11/233,814, filed Sep. 23, 2005, which is incorporated herein byreference in its entirety. However, in some patients it may be difficultor impractical to achieve such real-time monitoring when utilizingnon-thermal pulsed electric field neuromodulatory mechanisms. In somepatients, this may necessitate re-intervention the degree of inducedneuromodulation was not sufficient to achieve a desired treatmentoutcome. Conversely, an overly aggressive course of relativelyunmonitored or uncontrolled therapy may induce undesirable and/orpersistent damage in non-target tissue. Thus, it would be desirable toachieve renal neuromodulation via more easily monitored and/orcontrolled neuromodulatory mechanisms.

BRIEF DESCRIPTION OF THE DRAWINGS

Several embodiments of the present invention will be apparent uponconsideration of the following detailed description, taken inconjunction with the accompanying drawings, in which like referencecharacters refer to like parts throughout, and in which:

FIG. 1 is a schematic view illustrating human renal anatomy.

FIG. 2 is a schematic isometric detail view showing the location of therenal nerves relative to the renal artery.

FIG. 3 is a schematic side view, partially in section, illustrating anexample of an extravascular method and apparatus for thermal renalneuromodulation.

FIGS. 4A-4C are schematic side views, partially in section, illustratingexamples of intravascular methods and apparatus for thermal renalneuromodulation.

FIGS. 5A and 5B are schematic side views, partially in section,illustrating an alternative embodiment of the intravascular methods andapparatus of FIG. 4 comprising wall-contact electrodes.

FIGS. 6A and 6B are schematic side views, partially in section,illustrating an additional alternative embodiment of the intravascularmethods and apparatus of FIG. 4 comprising alternative wall-contactelectrodes.

FIGS. 7A and 7B are schematic side views, partially in section,illustrating other alternative embodiments of the intravascular methodsand apparatus of FIG. 4 comprising multiple wall-contact electrodes.

FIGS. 8A-8H are schematic side views, partially in section, illustratingembodiments of the intravascular methods and apparatus of FIG. 4comprising one or more wall-contact electrodes, as well as optionalblood flow occlusion and thermal fluid injection.

FIG. 9 is a schematic side view, partially in section, illustrating anexample of an intra-to-extravascular method and apparatus for thermalrenal neuromodulation.

FIG. 10 is a schematic side view, partially in section, of analternative embodiment of the method and apparatus of FIG. 8 configuredfor thermal renal neuromodulation via direct application of thermalenergy.

FIG. 11 is a schematic side view, partially in section, illustrating amethod and apparatus for thermal renal neuromodulation comprising athermoelectric element suitable for direct application of thermal energyto target neural fibers.

FIG. 12 is a schematic side view, partially in section, illustratinganother method and apparatus for thermal renal neuromodulationcomprising a thermoelectric element.

FIGS. 13A and 13B are schematic side views, partially in section,illustrating a method and apparatus for thermal renal neuromodulationvia high-intensity focused ultrasound.

FIG. 14 is a schematic side view, partially in section, illustrating analternative embodiment of the apparatus and method of FIG. 13.

FIGS. 15A and 15B are schematic diagrams for classifying the varioustypes of thermal neuromodulation that may be achieved with the apparatusand methods of the present invention.

FIG. 16 is a schematic side-view, partially in section, of anintravascular catheter having a plurality of electrodes in accordancewith one embodiment of the invention.

FIG. 17 is a schematic side-view, partially in section, of anintravascular device having a pair of expanding helical electrodesarranged at a desired distance from one another in accordance withanother embodiment of the invention.

FIG. 18 illustrates stimulation of renal nerves across the wall of arenal vein.

FIGS. 19A and 19B are side views, partially in section, illustrating anintravascular device having detectors for measuring or monitoringtreatment efficacy in accordance with another embodiment of theinvention.

DETAILED DESCRIPTION A. Overview

The following describes several embodiments of methods and apparatus forrenal neuromodulation via thermal heating and/or thermal coolingmechanisms. Many embodiments of such methods and apparatus may reducerenal sympathetic nerve activity. Thermally-induced (via heating and/orcooling) neuromodulation may be achieved via apparatus positionedproximate target neural fibers, such as being positioned (a) withinrenal vasculature (i.e., positioned intravascularly), (b)extravascularly, (c) intra-to-extravascularly, or (d) a combinationthereof. Thermal neuromodulation by heating or cooling may be caused bydirectly effecting or otherwise altering the neural structures that aresubject to the thermal stress. Additionally or alternatively, thethermal neuromodulation may at least in part be due to alteration ofarteries, arterioles, capillaries, or veins or other vascular structureswhich perfuse the target neural fibers or surrounding tissue. Furtherstill, the modulation may at least in part be caused by electroporationof the target neural fibers or of surrounding tissue.

As used herein, thermal heating mechanisms for neuromodulation includeboth thermal ablation and non-ablative thermal injury or damage (e.g.,via sustained heating or resistive heating). Thermal heating mechanismsmay include raising the temperature of target neural fibers above adesired threshold to achieve non-ablative thermal injury, or above ahigher temperature) to achieve ablative thermal injury. For example, thetarget temperature can be above body temperature (e.g., approximately37° C.) but less than about 45° C. for non-ablative thermal injury, orthe target temperature can be about 45° C. for the ablative thermalinjury.

As used herein, thermal cooling mechanisms for neuromodulation includenon-freezing thermal slowing of nerve conduction and/or non-freezingthermal nerve injury, as well as freezing thermal nerve injury. Thermalcooling mechanisms may include reducing the temperature of target neuralfibers below a desired threshold, for example, below the bodytemperature of about 37° C. (e.g., below about 20° C.) to achievenon-freezing thermal injury. Thermal cooling mechanisms also may includereducing the temperature of the target neural fibers below about 0° C.,e.g., to achieve freezing thermal injury.

In addition to monitoring or controlling the temperature during thermalneuromodulation, the length of exposure to thermal stimuli may bespecified to affect an extent or degree of efficacy of the thermalneuromodulation. In many embodiments, the length of exposure to thermalstimuli is longer than instantaneous exposure, such as longer than about30 seconds, or even longer than 2 minutes. In certain specificembodiments, the length of exposure can be less than 10 minutes, butthis should in no way be construed as the upper limit of the exposureperiod. Exposure times measured in hours, days or longer, may beutilized to achieve desired thermal neuromodulation.

When conducting neuromodulation via thermal mechanisms, the temperaturethreshold discussed previously may be determined as a function of theduration of exposure to thermal stimuli. Additionally or alternatively,the length of exposure may be determined as a function of the desiredtemperature threshold. These and other parameters may be specified orcalculated to achieve and control desired thermal neuromodulation.

In some embodiments, thermally-induced renal neuromodulation may beachieved by directly applying thermal cooling or heating energy to thetarget neural fibers. For example, a chilled or heated fluid can beapplied at least proximate to the target neural fiber, or heated orcooled elements (e.g., a thermoelectric element or a resistive heatingelement) can be placed in the vicinity of the neural fibers. In otherembodiments, thermally-induced renal neuromodulation may be achieved viaindirect generation and/or application of the thermal energy to thetarget neural fibers, such as through application of a ‘thermal’electric field, high-intensity focused ultrasound, laser irradiation,etc., to the target neural fibers. For example, thermally-induced renalneuromodulation may be achieved via delivery of a pulsed or continuousthermal electric field to the target neural fibers, the electric fieldbeing of sufficient magnitude and/or duration to thermally induce theneuromodulation in the target fibers (e.g., to heat or thermally ablateor necrose the fibers). Additional and alternative methods and apparatusmay be utilized to achieve thermally-induced renal neuromodulation, asdescribed hereinafter.

When utilizing thermal heating mechanisms for thermal neuromodulation,protective cooling elements, such as convective cooling elements,optionally may be utilized to protect smooth muscle cells or othernon-target tissue from undesired thermal effects during thethermally-induced renal neuromodulation. Likewise, when utilizingthermal cooling mechanisms, protective heating elements, such asconvective heating elements, may be utilized to protect the non-targettissue. Non-target tissue additionally or alternatively may be protectedby focusing the thermal heating or cooling energy on the target neuralfibers so that the intensity of the thermal energy outside of the targetzone is insufficient to induce undesired thermal effects in thenon-target tissue. When thermal neuromodulation is achieved via thermalenergy delivered intravascularly, the non-target tissue may be protectedby utilizing blood flow as a conductive and/or convective heat sink thatcarries away excess thermal energy (hot or cold). For example, whenblood flow is not blocked, the circulating blood may remove excessthermal energy from the non-target tissue during the procedure. Theintravascularly-delivered thermal energy may heat or cool target neuralfibers located proximate to the vessel to modulate the target neuralfibers while blood flow within the vessel protects non-target tissue ofthe vessel wall from the thermal energy. For example, the thermal energycan target neural fibers within the adventitia to necrose or ablate thetarget fibers, and the blood flow can protect tissue in the vessel wall.

One drawback of using a continuous, intravascularly-delivered thermalenergy therapy in the presence of blood flow to achieve desiredintravascularly-induced neuromodulation is that the feasible thermalmagnitude (e.g., power) and/or duration of the therapy may be limited orinsufficient. This can be caused by the limited heat capacity of theblood flowing through the blood vessel to remove excess thermal energyfrom the vessel wall to mitigate damage or necrosis to the non-targettissue. Pulsed RF electric fields or other type of pulsed thermal energymay facilitate greater thermal magnitude (e.g., higher power), longertotal duration and/or better controlled intravascular renalneuromodulation therapy compared to a continuous thermal energy therapy.For example, a pulsed thermal therapy may allow for monitoring ofeffects of the therapy on target or non-target tissue during theinterval between the pulses. This monitoring data optionally may be usedin a feedback loop to better control therapy, e.g., to determine whetherto continue or stop treatment, and it may facilitate controlled deliveryof a higher power or longer duration therapy.

Furthermore, the time interval between delivery of thermal energy pulsesmay facilitate additional convective or other cooling of the non-targettissue of the vessel wall compared to applying an equivalent magnitudeor duration of continuous thermal energy. Without being limited totheory, this may occur because blood flow through the blood vessel mayconvectively cool (heat) the non-target tissue of the vessel wall withwhich the blood contacts faster than target neural fibers positionedoutside of the vessel.

When providing a pulsed thermal therapy, this difference in the heattransfer rate between the tissue of the blood vessel wall and therelatively remote target neural fibers may be utilized to ablate,necrose or otherwise modulate the target neural fibers withoutundesirably affecting the non-target tissue. The pulsed thermal energytherapy may be applied with greater thermal magnitude and/or of longertotal duration (i.e., the cumulative duration of all thermal energypulses within the therapy) than a continuous thermal therapy. Heattransfer from the vessel wall to the blood (or vice versa) during theoff-time or low-energy interval between the thermal energy pulsesfacilitates the greater magnitude/longer duration delivery withmoderated damage to the non-target tissue.

In addition or as an alternative to utilizing the patient's blood as aheat sink to establish the difference in heat transfer rate, a thermalfluid (hot or cold) may be injected, infused or otherwise delivered intothe vessel to remove excess thermal energy and protect the non-targettissues. The thermal fluid may, for example, comprise a saline or otherbiocompatible fluid that is heated, chilled or at a room temperature.The thermal fluid may, for example, be injected through the devicecatheter or through a guide catheter at a location upstream from anenergy delivery element, or at other locations relative to the tissuefor which protection is sought. The thermal fluid may be injected in thepresence of blood flow or with the flow temporarily occluded.

Occlusion of flow in combination with thermal fluid delivery mayfacilitate good control over the heat transfer kinetics along thenon-target tissues. For example, the normal variability in blood flowrate between patients, which would vary the heat transfer capacity ofthe blood flow, may be controlled for by transferring thermal energybetween the vessel wall and a thermal fluid that is delivered at acontrolled rate. Use of injected thermal fluids to remove excess thermalenergy from non-target tissues to relatively protect the non-targettissues during therapeutic treatment of target tissues may be utilizedin body lumens other than blood vessels.

In some embodiments, methods and apparatus for real-time monitoring ofan extent or degree of neuromodulation or denervation (e.g., an extentor degree of thermal damage) in tissue innervated by the target neuralfibers and/or of thermal damage in the non-target tissue may beprovided. Likewise, real-time monitoring of the thermal energy deliveryelement may be provided. Such methods and apparatus may, for example,comprise a thermocouple or other temperature sensor for measuring thetemperature of the monitored tissue or of the thermal energy deliveryelement. Other parameters that can be measured include the power, totalenergy delivered, or impedance. Monitoring data may be used for feedbackcontrol of the thermal therapy. For example, intravascularly-deliveredthermal therapy may be monitored and controlled by acquiring temperatureor impedance measurements along the wall of the vessel in the vicinityof the treatment zone, and/or by limiting the power or duration of thetherapy.

To better understand the structures of several embodiments of devicesdescribed below, as well as the methods of using such devices forthermally-induced renal neuromodulation, a description of the renalanatomy in humans is provided.

B. Renal Anatomy Summary

With reference to FIG. 1, the human renal anatomy includes the kidneysK, which are supplied with oxygenated blood by the renal arteries RA.The renal arteries are connected to the heart via the abdominal aortaAA. Deoxygenated blood flows from the kidneys to the heart via the renalveins RV and the inferior vena cava IVC.

FIG. 2 illustrates a portion of the renal anatomy in greater detail.More specifically, the renal anatomy also includes renal nerves RNextending longitudinally along the lengthwise dimension L of renalartery RA, generally within the adventitia of the artery. The renalartery RA has smooth muscle cells SMC that surround the arterialcircumference and spiral around the angular axis 9 of the artery. Thesmooth muscle cells of the renal artery accordingly have a lengthwise orlonger dimension extending transverse (i.e., non-parallel) to thelengthwise dimension of the renal artery. The misalignment of thelengthwise dimensions of the renal nerves and the smooth muscle cells isdefined as “cellular misalignment.”

C. Embodiments of Apparatus and Methods for Neuromodulation

FIGS. 3-14 illustrate examples of systems and methods forthermally-induced renal neuromodulation. FIG. 3 shows one embodiment ofan extravascular apparatus 200 that includes one or more electrodesconfigured to deliver a thermal electric field to renal neural fibersfor renal neuromodulation via heating. The apparatus 200 of FIG. 3 isconfigured for temporary extravascular placement; however, it should beunderstood that partially or completely implantable extravascularapparatus additionally or alternatively may be utilized. Applicants havepreviously described extravascular pulsed electric field systems, forexample, in co-pending U.S. patent application Ser. No. 11/189,563,filed Jul. 25, 2005, which has been incorporated herein by reference inits entirety.

The specific embodiment of the apparatus 200 shown in FIG. 3 comprises alaparoscopic or percutaneous system having a probe 210 configured forinsertion in proximity to the track of the renal neural supply along therenal artery, vein, hilum and/or within Gerota's fascia under a suitableguidance system. The probe 210 can have at least one electrode 212 fordelivering a thermal electric field therapy. The electrode(s) 212, forexample, may be mounted on a catheter and electrically coupled to athermal electric field generator 50 via wires 211. The electrode 212 canbe passed through the probe 210, or in an alternative embodimentelectrode 212 may be mounted to the probe 210. The probe 210 may have anelectrical connector to couple the electrode 212 to the field generator50.

The field generator 50 is located external to the patient. Thegenerator, as well as any of the electrode embodiments described herein,may be utilized with any embodiment of the present invention fordelivery of a thermal electric field with desired field parameters,e.g., parameters sufficient to thermally or otherwise induce renalneuromodulation in target neural fibers via heating and/orelectroporation. It should be understood that electrodes of embodimentsdescribed hereinafter may be electrically connected to the generatoreven though the generator is not explicitly shown or described with eachembodiment. Furthermore, the field generator optionally may bepositioned internally within the patient. Further still, the fieldgenerator may additionally comprise or may be substituted with analternative thermal energy generator, such as a thermoelectric generatorfor heating or cooling (e.g., a Peltier device), or a thermal fluidinjection system for heating or cooling, etc.

The electrode(s) 212 can be individual electrodes that are electricallyindependent of each other, a segmented electrode with commonly connectedcontacts, or a continuous electrode. A segmented electrode may, forexample, be formed by providing a slotted tube fitted onto theelectrode, or by electrically connecting a series of individualelectrodes. Individual electrodes or groups of electrodes 212 may beconfigured to provide a bipolar signal. The electrodes 212 may bedynamically assignable to facilitate monopolar and/or bipolar energydelivery between any of the electrodes and/or between any of theelectrodes and a remote electrode. Such a remote electrode may beattached externally to the patient's skin, e.g., to the patient's leg orflank. In FIG. 3, the electrodes 212 comprise a bipolar electrode pair.The probe 210 and the electrodes 212 may be similar to the standardneedle or trocar-type used clinically for RF nerve block. Alternatively,the apparatus 200 may comprise a flexible and/or custom-designed probefor the renal application described herein.

In FIG. 3, the probe 210 has been advanced through a percutaneous accesssite P into proximity with a patient's renal artery RA. The probepierces the patient's Gerota's fascia F, and the electrodes 212 areadvanced into position through the probe and along the annular spacebetween the patient's artery and fascia. Once properly positioned, thetarget neural fibers may be heated via a pulsed or continuous electricfield delivered across the bipolar electrodes 212. Such heating may, forexample, ablate or cause non-ablative thermal injury to the targetneural fibers to at least partially denervate the kidney innervated bythe target neural fibers. The electric field also may induce reversibleor irreversible electroporation in the target neural fibers, which maycompliment the thermal injury induced in the neural fibers. Aftertreatment, the apparatus 200 may be removed from the patient to concludethe procedure.

Referring now to FIGS. 4A and 4B, several embodiments of intravascularsystems for thermally-induced renal neuromodulation are described.Applicants have previously described intravascular pulsed electric fieldsystems, for example, in co-pending U.S. patent application Ser. No.11/129,765, filed May 13, 2005, which has been incorporated herein byreference in its entirety. The embodiments of FIGS. 4A and 4B areapparatus 300 comprising a catheter 302 having an optional positioningelement 304, shaft electrodes 306 a and 306 b disposed along the shaftof the catheter, and optional radiopaque markers 308 disposed along theshaft of the catheter in the region of the positioning element 304. Thepositioning element 304 can be a balloon, an expandable wire basket,other mechanical expander that holds the electrodes 306 a-b at a desiredlocation in the vessel. The electrodes 306 a-b can be arranged such thatthe electrode 306 a is near a proximal end of the positioning element304 and the electrode 306 b is near the distal end of the positioningelement 304. The electrodes 306 are electrically coupled to the fieldgenerator 50 (see FIG. 3) for delivery of a thermal electric field forheating of target neural fibers. In an alternative embodiment, one ormore of the electrodes may comprise Peltier electrodes for cooling thetarget neural fibers to modulate the fibers.

The positioning element 304 optionally may center or otherwise positionthe electrodes 306 a and 306 b within a vessel. Additionally, as in FIG.4A, the positioning element may comprise an impedance-altering elementthat alters the impedance between electrodes 306 a and 306 b during thetherapy to direct the thermal electric field across the vessel wall.This may reduce an energy required to achieve desired renalneuromodulation and may reduce a risk of undesirably affectingnon-target tissue. Applicants have previously described use of asuitable impedance-altering element in co-pending U.S. patentapplication Ser. No. 11/266,993, filed Nov. 4, 2005, which isincorporated herein by reference in its entirety. When the positioningelement 304 comprises an inflatable balloon as in FIG. 4A, the balloonmay serve as both a centering element for the electrodes 306 and as animpedance-altering electrical insulator for directing an electric fielddelivered across the electrodes, e.g., for directing the electric fieldinto or across the vessel wall for modulation of target neural fibers.Electrical insulation provided by the positioning element 304 may reducethe magnitude of applied energy or other parameters of the thermalelectric field necessary to achieve desired heating at the targetfibers.

Furthermore, the positioning element 304 optionally may be utilized as acooling element and/or a heating element. For example, the positioningelement 304 may be inflated with a chilled fluid that serves as a heatsink for removing heat from tissue that contacts the element.Conversely, the positioning element 304 optionally may be a heatingelement by inflating it with a warmed fluid that heats tissue in contactwith the element. The thermal fluid optionally may be circulated and/orexchanged within the positioning element 304 to facilitate moreefficient conductive and/or convective heat transfer. Thermal fluidsalso may be used to achieve thermal neuromodulation via thermal coolingor heating mechanisms, as described in greater detail herein below. Thepositioning element 304 (or any other portion of apparatus 300)additionally or alternatively may comprise one or more sensors formonitoring the process. In one embodiment, the positioning element 304has a wall-contact thermocouple 310 (FIG. 4A) for monitoring thetemperature or other parameters of the target tissue, the non-targettissue, the electrodes, the positioning element and/or any other portionof the apparatus 300.

The electrodes 306 can be individual electrodes (i.e., independentcontacts), a segmented electrode with commonly connected contacts, or asingle continuous electrode. Furthermore, the electrodes 306 may beconfigured to provide a bipolar signal, or the electrodes 306 may beused together or individually in conjunction with a separate patientground pad for monopolar use. As an alternative or in addition toplacement of the electrodes 306 along the central shaft of the catheter302, as in FIGS. 4A and 4B, the electrodes 306 may be attached to thepositioning element 304 such that they contact the wall of the renalartery RA. In such a variation, the electrodes may, for example, beaffixed to the inside surface, outside surface or at least partiallyembedded within the wall of the positioning element. FIG. 4C, describedhereinafter, illustrates one example of wall-contact electrodes, whileFIGS. 5-8 illustrate alternative wall-contact electrodes.

In use, the catheter 302 may be delivered to the renal artery RA asshown, or it may be delivered to a renal vein or to any other vessel inproximity to neural tissue contributing to renal function, in a lowprofile delivery configuration through a guide catheter or other device.Alternatively, catheters may be positioned in multiple vessels forthermal renal neuromodulation, e.g., within both the renal artery andthe renal vein. Techniques for pulsed electric field renalneuromodulation in multiple vessels have been described previously, forexample, in co-pending U.S. patent application Ser. No. 11/451,728,filed Jul. 12, 2006, which is incorporated herein by reference in itsentirety.

Once the positioning element 304 is at a desired location within therenal vasculature, it may be expanded into contact with an interior wallof the vessel. A thermal electric field then may be delivered via theelectrodes 306 across the wall of the artery. The electric fieldthermally modulates the activity along neural fibers that contribute torenal function via heating. In several embodiments, the thermalmodulation at least partially denervates the kidney innervated by theneural fibers via heating. This may be achieved, for example, viathermal ablation or non-ablative damage of the target neural fibers. Theelectric field also may induce electroporation in the neural fibers.

In the embodiment of FIG. 4A, the positioning element 304 illustrativelycomprises an inflatable balloon, which may preferentially direct theelectric field as discussed. In the embodiment of FIG. 4B, thepositioning element comprises an expandable wire basket thatsubstantially centers the electrodes 306 within the vessel withoutblocking blood flow through the vessel. During delivery of the thermalelectric field (or of other thermal energy), the blood may act as a heatsink for conductive and/or convective heat transfer to remove excessthermal energy from the non-target tissue. This protects the non-targettissue from undesired thermal effects. This effect may be enhanced whenblood flow is not blocked during energy delivery, as in the embodimentof FIG. 4B.

Using the patient's blood as a heat sink is expected to facilitatedelivery of longer or greater magnitude thermal treatments with reducedrisk of undesired effects to the non-target tissue, which may enhancethe efficacy of the treatment at the target neural fibers. Although theembodiment of FIG. 4B illustratively comprises a positioning element forcentering the electrodes without blocking flow, it should be understoodthat the positioning element may be eliminated and/or that theelectrodes may be attached to the positioning element such that they arenot centered in the vessel upon expansion of the centering element. Insuch embodiments, the patient's blood may still mitigate excess thermalheating or cooling to protect non-target tissues.

One drawback of using a continuous, intravascularly-delivered thermalenergy therapy in the presence of blood flow to achieve desiredintravascularly-induced neuromodulation is that the feasible thermalmagnitude (e.g., power) and/or duration of the therapy may be limited orinsufficient. This can occur because the capacity of the blood to removeheat is limited, and thus the blood flowing through the blood vessel maynot remove enough excess thermal energy from the vessel wall to mitigateor avoid undesirable effect in the non-target tissue. Use of a pulsedthermal energy therapy, such as a pulsed thermal RF electric field, mayfacilitate greater thermal magnitude (e.g., higher power), longer totalduration and/or better controlled intravascular renal neuromodulationtherapy compared to a continuous thermal energy therapy. For example,the effects of the therapy on target or non-target tissue may bemonitored during the intervals between the pulses. This monitoring dataoptionally may be used in a feedback loop to better control the therapy,e.g., to determine whether to continue or stop treatment, and it mayfacilitate controlled delivery of a higher power or longer durationtherapy.

Furthermore, the off-time or low-energy intervals between thermal energypulses may facilitate additional convective or other cooling of thenon-target tissue of the vessel wall compared to use of a continuousthermal therapy of equivalent magnitude or duration. This may occurbecause blood flow through the blood vessel can convectively cool (heat)the non-target tissue of the vessel wall faster than the target neuralfibers positioned outside of the vessel wall.

When providing a pulsed thermal therapy, the difference in heat transferrates between tissue of the blood vessel wall and the relatively remotetarget neural fibers may be utilized to ablate, necrose or otherwisemodulate the target neural fibers without producing undesirable effectsin the non-target tissue. As a result, the pulsed thermal energy therapymay be applied with greater thermal magnitude and/or of longer totalduration (i.e., the cumulative duration of all thermal energy pulses)compared to a continuous thermal therapy. The higher heat transfer rateat the vessel wall during the intervals between the thermal energypulses facilitates the greater magnitude/longer duration delivery.

In addition or as an alternative to utilizing the patient's blood as aheat sink to create a difference in the heat transfer rate, a thermalfluid (hot or cold) may be injected, infused or otherwise delivered intothe vessel to remove excess thermal energy and protect the non-targettissues. The thermal fluid may, for example, comprise saline or anotherbiocompatible fluid that is heated, chilled or at room temperaturesaline. The thermal fluid may, for example, be injected through thedevice catheter or through a guide catheter at a location upstream froman energy delivery element, or at other locations relative to the tissuefor which protection is sought. The thermal fluid may be injected in thepresence of blood flow or with the blood flow temporarily occluded.

In several embodiments, the occlusion of the blood flow in combinationwith thermal fluid delivery may facilitate good control over the heattransfer kinetics along the non-target tissues. For example, the normalvariability in blood flow rate between patients, which would vary theheat transfer capacity of the blood flow, may be controlled for bytransferring thermal energy between the vessel wall and a thermal fluidthat is delivered at a controlled rate. Furthermore, this method ofusing an injected thermal fluid to remove excess thermal energy fromnon-target tissues in order to protect the non-target tissues duringtherapeutic treatment of target tissues may be utilized in body lumensother than blood vessels.

One or more sensors, such as the thermocouple 310 of FIG. 4A, may beused to monitor the temperature(s) or other parameter(s) at theelectrodes 306, the wall of the vessel and/or at other desired locationsalong the apparatus or the patient's anatomy. The thermalneuromodulation may be controlled using the measured parameter(s) asfeedback. This feedback may be used, for example, to maintain theparameter(s) below a desired threshold. For example, the parameter(s)may be maintained below a threshold that may cause undesired effects inthe non-target tissues. With blood flowing through the vessel, morethermal energy may be carried away, which may allow for longer or higherenergy treatments than when blood flow is blocked in the vessel.

As discussed, when utilizing intravascular apparatus to achieve thermalneuromodulation, in addition or as an alternative to central positioningof the electrode(s) within a blood vessel, the electrode(s) optionallymay be configured to contact an internal wall of the blood vessel.Wall-contact electrode(s) may facilitate more efficient transfer of athermal electric field across the vessel wall to target neural fibers,as compared to centrally-positioned electrode(s). In some embodiments,the wall-contact electrode(s) may be delivered to the vessel treatmentsite in a reduced profile configuration, then expanded in vivo to adeployed configuration wherein the electrode(s) contact the vessel wall.In some embodiments, expansion of the electrode(s) is at least partiallyreversible to facilitate retrieval of the electrode(s) from thepatient's vessel.

FIG. 4C depicts an embodiment of an apparatus 400 having one or morewall-contact electrodes 306. One or more of the struts of the expandablebasket positioning element 304 may comprise a conductive material thatis insulated in regions other than along segments that contact thevessel wall and form electrode(s) 306. The electrode(s) may be used ineither a bipolar or a monopolar configuration. Furthermore, theelectrode(s) may comprise sensor(s), e.g., impedance or temperaturesensors, for monitoring and/or controlling the effects of the thermalenergy delivery. The sensors, for example, can be thermocouples.

FIGS. 5A and 5B depict an alternative embodiment of intravascularapparatus 500 having electrodes configured to contact the interior wallof a vessel. The apparatus 500 of FIGS. 5A and 5B is an alternativeembodiment of the apparatus 300 of FIGS. 4A and 4B wherein the proximalelectrode 306 a of FIGS. 4A and 4B has been replaced with wall-contactelectrode 306 a′. The wall-contact electrode comprises proximalconnector 312 a that connects the electrode to the shaft of the catheter302 and is electrically coupled to the pulse generator. The apparatus500 also has a plurality of extensions 314 a that extend from theproximal connector 312 a and at least partially extend over a surface ofpositioning element 304. The extensions 314 a optionally may beselectively insulated such that only a selective portion of theextensions, e.g., the distal tips of the extensions, are electricallyactive. The electrode 306 a′ optionally may be fabricated from a slottedtube, such as a stainless steel or shape-memory (e.g., NiTi) slottedtube. Furthermore, all or a portion of the electrode may be gold-platedto improve radiopacity and/or conductivity.

As seen in FIG. 5A, the catheter 302 may be delivered over a guidewire Gto a treatment site within the patient's vessel with the electrode 306a′ positioned in a reduced profile configuration. The catheter 302optionally may be delivered through a guide catheter 303 to facilitatesuch reduced profile delivery of the wall-contact electrode. Whenpositioned as desired at a treatment site, the electrode 306 a′ may beexpanded into contact with the vessel wall by expanding the positioningelement 304 (shown in FIG. 5B). A thermal monopolar or bipolar electricfield then may be delivered across the vessel wall and between theelectrodes 306 a′ and 306 b to induce thermal neuromodulation, asdiscussed previously. The optional positioning element 304 may alterimpedance within the blood vessel and more efficiently route theelectrical energy across the vessel wall to the target neural fibers.

After terminating the electric field, the electrode 306 a′ may bereturned to a reduced profile and the apparatus 300 may be removed fromthe patient or repositioned in the vessel. For example, the positioningelement 304 may be collapsed (e.g., deflated), and the electrode 306 a′may be contracted by withdrawing the catheter 302 within the guidecatheter 303. Alternatively, the electrode may be fabricated from ashape-memory material biased to the collapsed configuration, such thatthe electrode self-collapses upon collapse of the positioning element.

Although in FIGS. 5A and 5B the electrode 306 a′ is expanded intocontact with the vessel wall, it should be understood that the electrodealternatively may be fabricated from a self-expanding material biasedsuch that the electrode self-expands into contact with the vessel wallupon positioning of the electrode distal of the guide catheter 303. Aself-expanding embodiment of the electrode 306 a′ may obviate a need forthe positioning element 304 and/or may facilitate maintenance of bloodflow through the blood vessel during delivery of an electric field viathe electrode. After delivery of the electric field, the self-expandingelectrode 306 a′ may be returned to a reduced profile to facilitateremoval of the apparatus 300 from the patient by withdrawing thecatheter 302 within the guide catheter 303.

FIGS. 6A and 6B depict another embodiment of an apparatus 600 andmethods for delivering a field using a wall-contact electrode. As analternative to the proximal connector 312 a of the electrode 306 a′ ofFIGS. 5A and 5B, the electrode 306 a″ of FIG. 6 comprises a distalconnector 316 a for coupling the electrode to the shaft of catheter 302on the distal side of the positioning element 304. The distal connectorenables the electrode to extend over the entirety of the positioningelement 304 and may facilitate contraction of the electrode 306 a″ afterthermal neuromodulation. For example, the electrode 306 a″ can becontracted by proximally retracting the proximal connector 312 arelative to the catheter 302 during or after contraction of thepositioning element 304. FIG. 6A shows the electrode 306 a″ in thereduced profile configuration, and FIG. 6B shows the electrode in theexpanded in which the conductive portions contact the vessel wall.

FIGS. 7A and 7B show additional alternative embodiments of methods andan apparatus 700. In FIGS. 7A and 7B, the apparatus 700 comprises theproximal electrode 306 a′ of FIGS. 5A and 5B, and a distal wall-contactelectrode 306 b′. The embodiment of FIG. 7A comprises proximal anddistal positioning elements 304 a and 304 b, respectively, for expandingthe proximal and distal wall-contact electrodes 306 a′ and 306 b′,respectively, into contact with the vessel wall. The embodiment of FIG.7B comprises only a single positioning element 304, but the distalwall-contact electrode 306 b′ is proximal facing and positioned over thedistal portion of the positioning element 304 to facilitate expansion ofthe distal electrode 306 b′. In the embodiment of FIG. 7B, theextensions of the proximal and distal electrodes optionally may beconnected along non-conductive connectors 318 to facilitate collapse andretrieval of the electrodes post-treatment.

A bipolar electric field may be delivered between the proximal anddistal wall-contact electrodes, or a monopolar electric field may bedelivered between the proximal and/or distal electrode(s) and anexternal ground. Having both the proximal and distal electrodes incontact with the wall of the vessel may facilitate more efficient energytransfer across the wall during delivery of a thermal electric field, ascompared to having one or both of the proximal and distal electrodescentered within the vessel.

FIGS. 8A-8H illustrate additional embodiments of the apparatus andmethods that can comprise one or more wall-contact electrodes, bloodflow occlusion features, and thermal fluid injection functions. Theembodiments of FIG. 8 are described as monopolar devices, but it shouldbe understood that any or all of the embodiments may be configured oroperated as bipolar devices. Furthermore, although blood flow occlusionand thermal fluid injection are described in combination withwall-contact electrode(s), it should be understood that such occlusionand injection features may be provided in combination with electrode(s)that do not contact the vessel wall.

As discussed previously, in addition or as an alternative to utilizingthe patient's blood as a heat sink to create different heat transferrates between target neural fibers and non-target tissue of the wall ofthe vessel within which thermal energy is delivered, a thermal fluid(hot or cold) may be injected, infused or otherwise delivered into thevessel. The thermal fluid may further remove excess thermal energy andprotect the non-target tissues. When delivering thermal RF therapy, thethermal fluid may, for example, comprise chilled or room temperaturesaline (e.g., saline at a temperature lower than the temperature of thevessel wall during the therapy delivery). The thermal fluid may beinjected through the device catheter or through a guide catheter at alocation upstream from an energy delivery element, or at other locationsrelative to the tissue for which protection is sought. The thermal fluidmay be injected in the presence of blood flow or with blood flowtemporarily occluded. The occlusion of blood flow in combination withthermal fluid delivery may facilitate good control over the heattransfer kinetics along the non-target tissues, as well as injection offluid from a downstream location.

FIGS. 8A and 8B show an embodiment of an apparatus 800 a that comprisesthe catheter 802 having an element 804, which may be used to positionthe apparatus within the vessel and/or to occlude blood flow. Theelement 304 can be an inflatable balloon. The apparatus 800 can furtherhave an active monopolar electrode 806 located proximally from theelement 304 such that inflation of the element 304 blocks blood flowdownstream of the electrode 806. The monopolar electrode 806illustratively comprises multiple extensions 814, and it should beunderstood that any desired number of extensions may be provided,including a single extension. The monopolar electrode is utilized incombination with a remote electrode, such as a ground pad, positionedexternal to the patient. The apparatus can also comprise an infusionport 805 between the element 804 and the monopolar electrode 806.

In FIG. 8A, the catheter 802 may be advanced within the renal artery RAin a reduced profile delivery configuration. In FIG. 8B, once properlypositioned, the electrode 806 may be actively expanded, or it mayself-expand by removing a sheath, the guide catheter or another type ofrestraint from the electrode. The expanded electrode 806 contacts thevessel wall. The element 804 may be expanded (before, during or afterexpansion of the electrode) to properly position the electrode withinthe vessel and/or to occlude blood flow within the renal arterydownstream of the electrode. A monopolar electric field may be deliveredbetween the active electrode 806 and the external ground. The electricfield may, for example, comprise a pulsed or continuous RF electricfield that thermally induces neuromodulation (e.g., necrosis orablation) in the target neural fibers. The thermal therapy may bemonitored and controlled, for example, via data collected withthermocouples 810, impedance sensors or other sensors.

To increase the power that may be delivered or the duration of thethermal treatment without undesirably affecting non-target tissue, athermal fluid infusate I may be injected through injection port 805 ofthe catheter 802 to cool (heat) the non-target tissue. This is expectedto mitigate undesired effects in the non-target tissue. The infusatemay, for example, comprise chilled saline that removes excess thermalenergy (hot or cold) from the wall of the vessel during thermal RFtherapy.

Convective or other heat transfer between the non-target vessel walltissue and the infusate I may facilitate cooling (heating) of the vesselwall at a faster rate than cooling (heating) occurs at the target neuralfibers. This difference in the heat transfer rates between the wall ofthe vessel and the target neural fibers may be utilized to modulate theneural fibers. Furthermore, when utilizing a pulsed thermal therapy, theaccelerated heat transfer at the wall relative to the neural fibers mayallow for relatively higher power or longer duration therapies (ascompared to continuous thermal therapies). Also, the interval betweenpulses may be used to monitor and/or control effects of the therapy.

FIG. 8C shows an embodiment of another apparatus 801 with wall-contactelectrodes, flow occlusion and thermal fluid injection. In FIG. 8C, theocclusion element 804 is coupled to the guide wire G, which may comprisean inflation lumen, and the infusate I is delivered through a distaloutlet of the catheter 802. As will be apparent, the occlusion elementalternatively may be coupled to a separate catheter or sheath ratherthan to the guide wire. Also, the infusate may, for example, bedelivered through the guide wire lumen or through an additional lumen orannulus of the catheter 802. FIG. 8D illustrates another embodiment ofan apparatus 830 wherein the occlusion element 804 is positionedproximal or upstream of the electrode(s) 806, and the infusate I isdelivered at a position distal of the occlusion element but proximal ofthe electrode(s). [Ken: Make numbering changes in text to correspond tofigures.]

FIG. 8E is an embodiment of apparatus 804 with occlusion elements 804positioned both proximal and distal of the electrode(s) 306. In additionto having a first injection port 305 a, the catheter 302 comprises anaspiration port 305 b. Separate lumens can extend through the catheterfor injection and aspiration of the infusate I via the ports 305.Providing both injection and aspiration of the infusate facilitates goodcontrol over the flow dynamics of the infusate, and thereby the heattransfer kinetics of the infusate. For example, providing aspiration andinjection at the same rate may provide consistent heat transfer kineticsbetween the vessel and the electrode(s).

FIG. 8F illustrates another embodiment of an apparatus 850 having acatheter 852 comprising a wall-contact electrode 856 that may be movedinto contact with the vessel wall via an elongated member 857. In thisembodiment, the elongated member 857 is distally connected to thecatheter in the vicinity of the electrode 306. The elongated member maybe configured for self expansion, or it may extend through port 305 ofthe catheter 302 and through a lumen of the catheter to a proximallocation for manipulation by a medical practitioner. The proximalsection of the elongated member may be advanced relative to the catheter302 by the medical practitioner such that the member assumes theillustrated curved profile.

Upon expansion of the elongated member, the catheter 302 is deflectedsuch that the electrode 306 coupled to the catheter shaft contacts thevessel wall. Optionally, element 304 may be expanded to facilitatepositioning of the electrode via the elongated member and/or to blockflow through the vessel. The element 304 can be coupled to the guide ordelivery catheter 303. Infusate I optionally may be delivered throughthe catheter 303 as shown.

FIG. 8G is an embodiment of an apparatus 860 comprising a shaped orself-expanding electrode 866. The electrode 866 may be delivered to atreatment site within catheter 303, and then it moves to a preselectedshape after it has been removed from the lumen of the catheter 303. Forexample, the electrode 866 can be removed from the catheter by advancingthe catheter 302 and/or retracting the catheter 303. The electrode 866contacts the vessel wall for delivery of therapy. Optionally, catheter302 may be rotated to rotate the electrode relative to the vessel walland angularly reposition the electrode. The therapy may be delivered ata singular angular position or at multiple angular positions.Additionally or alternatively, multiple angularly spaced electrodes 306may be positioned within the vasculature, as shown in FIG. 8H. Inaddition to angular spacing, the electrodes may be longitudinally spacedto facilitate treatment over a longitudinal segment of the vessel, e.g.,to achieve a circumferential treatment along the longitudinal segmentrather than along a cross-section.

In addition to extravascular and intravascular systems forthermally-induced renal neuromodulation, intra-to-extravascular systemsmay be provided. The intra-to-extravascular systems may, for example,have electrode(s) that are delivered to an intravascular position, andthen at least partially passed through/across the vessel wall to anextravascular position prior to delivery of a thermal electric field.Intra-to-extravascular positioning of the electrode(s) may place theelectrode(s) in closer proximity to target neural fibers for delivery ofa thermal electric field, as compared to fully intravascular positioningof the electrode(s). Applicants have previously describedintra-to-extravascular pulsed electric field systems, for example, inco-pending U.S. patent application Ser. No. 11/324,188, filed Dec. 29,2005, which is incorporated herein by reference in its entirety.

FIG. 9 illustrates one embodiment of an intra-to-extravascular (“ITEV”)system for thermally-induced renal neuromodulation is described. ITEVsystem 900 comprising a catheter 922 having (a) a plurality of proximalelectrode lumens terminating at proximal side ports 924, (b) a pluralityof distal electrode lumens terminating at distal side ports 926, and (c)a guidewire lumen 923. The catheter 922 preferably comprises an equalnumber of proximal and distal electrode lumens and side ports. The ITEVsystem 900 also includes proximal needle electrodes 928 that may beadvanced through the proximal electrode lumens and the proximal sideports 924, as well as distal needle electrodes 929 that may be advancedthrough the distal electrode lumens and the distal side ports 926.

The catheter 922 comprises an optional expandable positioning element930, which may comprise an inflatable balloon or an expandable basket orcage. In use, the positioning element 930 may be expanded prior todeployment of the needle electrodes 928 and 929 in order to position orcenter the catheter 922 within the patient's vessel (e.g., within renalartery RA). Centering the catheter 922 is expected to facilitatedelivery of all needle electrodes to desired depths within/external tothe patient's vessel (e.g., to deliver all of the needle electrodesapproximately to the same depth). In FIG. 9, the illustrated positioningelement 930 is between the proximal side ports 924 and the distal sideports 926, and thus the positioning element 930 is between the deliverypositions of the proximal and distal electrodes. However, it should beunderstood that the positioning element 930 additionally oralternatively may be positioned at a different location or at multiplelocations along the length of the catheter 922 (e.g., at a locationproximal of the side ports 924 and/or at a location distal of the sideports 926).

As illustrated in FIG. 9, the catheter 922 may be advanced to atreatment site within the patient's vasculature over a guidewire (notshown) via the lumen 323. During intravascular delivery, the electrodes928 and 929 may be positioned such that their non-insulated andsharpened distal regions are positioned within the proximal and distallumens, respectively. Once at a treatment site, a medical practitionermay advance the electrodes via their proximal regions that are locatedexternal to the patient. Such advancement causes the distal regions ofthe electrodes 928 and 929 to exit side ports 924 and 926, respectively,and pierce the wall of the patient's vasculature such that theelectrodes are positioned extravascularly via an ITEV approach.

The proximal electrodes 928 can be connected to an electric fieldgenerator 50 as active electrodes, and the distal electrodes 929 canserve as return electrodes. In this manner, the proximal and distalelectrodes form bipolar electrode pairs that align the thermal electricfield with a longitudinal axis or direction of the patient'svasculature. As will be apparent, the distal electrodes 929alternatively may comprise the active electrodes and the proximalelectrodes 928 may comprise the return electrodes. Furthermore, theproximal and/or the distal electrodes may comprise both active andreturn electrodes. Further still, the proximal and/or the distalelectrodes may be utilized in combination with an external ground fordelivery of a monopolar thermal electric field. Any combination ofactive and distal electrodes may be utilized, as desired.

When the electrodes 928 and 929 are connected to an electric fieldgenerator and positioned extravascularly, and with the positioningelement 930 optionally expanded, delivery of the thermal electric fieldmay proceed to achieve desired renal neuromodulation via heating. Theelectric field also may induce electroporation. After achievement of thethermally-induced renal neuromodulation, the electrodes may be retractedwithin the proximal and distal lumens, and the positioning element 930may be collapsed for retrieval. The ITEV system 920 then may be removedfrom the patient to complete the procedure. Additionally oralternatively, the system may be repositioned to provide therapy atanother treatment site, such as to provide bilateral renalneuromodulation.

Cooling elements, such as convective cooling elements, may be utilizedto protect non-target tissues like smooth muscle cells from thermaldamage during thermally-induced renal neuromodulation via heatgeneration. Non-target tissues may be protected by focusing the thermalenergy on the target neural fibers such that an intensity of the thermalenergy is insufficient to induce thermal damage in non-target tissuesdistant from the target neural fibers.

Although FIGS. 3-7 and 9 illustratively show bipolar apparatus, itshould be understood that monopolar apparatus alternatively may beutilized as in FIGS. 8A-8H. For example, an active monopolar electrodemay be positioned intravascularly, extravascularly orintra-to-extravascularly in proximity to target neural fibers thatcontribute to renal function. A return electrode may be attached to theexterior of the patient or positioned in the patient apart from theactive electrodes. Finally, a thermal electric field may be deliveredbetween the in vivo monopolar electrode and the remote electrode toeffectuate desired thermally-induced renal neuromodulation. Monopolarapparatus additionally may be utilized for bilateral renalneuromodulation.

The embodiments of FIGS. 3-9 illustratively describe methods andapparatus for thermally-induced renal neuromodulation via delivery ofthermal electric fields that modulate the target neural fibers. However,it should be understood that alternative methods and apparatus forthermally-induced (via both heating and cooling) renal neuromodulationmay be provided. For example, electric fields may be used to cool andmodulate the neural fibers with thermoelectric or Peltier elements.Also, thermally-induced renal neuromodulation optionally may be achievedvia direct application of thermal energy to the target neural fibers.Such direct thermal energy may be generated and/or transferred in avariety of ways, such as via resistive heating, via delivery of a heatedor chilled fluid (see FIGS. 10 and 12), via a Peltier element (see FIG.11), etc. Thermally-induced renal neuromodulation additionally oralternatively may be achieved via application of high-intensity focusedultrasound to the target neural fibers (see FIG. 13). Additional andalternative methods and apparatus for thermally-induced renalneuromodulation may be used in accordance with the present invention.

With reference now to FIG. 10, an alternative embodiment of an apparatus1000 and methods for thermally-induced neuromodulation via directapplication of thermal energy is described. In the embodiment of FIG.10, the electrodes 328 and 329 of FIG. 9 have been replaced withinfusion needles 1028 and 1029, respectively. A thermal fluid F may bedelivered through the needles to the target neural fibers. The thermalfluid may be heated in order to raise the temperature of the targetneural fibers above a desired threshold. For example, the temperature ofthe neural fibers can be raised above a body temperature of about 37°C., or above a temperature of about 45° C. Alternatively, the thermalfluid may be chilled to reduce the temperature of the target neuralfibers below a desired threshold. For example, the neural fibers can becooled to below the body temperature of about 37° C., or further cooledbelow about 20° C., or still further cooled below a freezing temperatureof about 0° C. As will be apparent, in addition tointra-to-extravascular delivery of a thermal fluid, the thermal fluidmay be delivered intravascularly (e.g., may inflate and/or be circulatedthrough a balloon member), extravascularly (e.g., may be circulatedthrough a vascular cuff), or a combination thereof.

In addition or as alternative to injection of a thermal fluid to thetarget neural fibers through infusion needles 1028 and 1029, analternative neuromodulatory agent, such as a drug or medicament, may beinjected to modulate, necrose or otherwise block or reduce transmissionalong the target neural fibers. Examples of alternative neuromodulatoryagents include, but are not limited to, phenol and neurotoxins, such asbotulinum toxin. Additional neuromodulatory agents, per se known, willbe apparent to those of skill in the art.

FIG. 11 shows another method and apparatus 110 for thermal renalneuromodulation via direct application of thermal energy to the targetneural fibers. The apparatus 1100 comprises renal artery cuff 1102having one or more integrated thermoelectric elements that areelectrically coupled to an internal or external power supply 1104. Thethermoelectric element utilizes the well-known Peltier effect (i.e., theestablishment of a thermal gradient induced by an electric voltage) toachieve thermal renal neuromodulation.

An electric current is passed from the power supply 1104 to thethermoelectric element of the cuff 1102. The thermoelectric element cancomprise two different metals (e.g., a p-type and an n-typesemiconductor) that are connected to each other at two junctions. Thecurrent induces a thermal gradient between the two junctions, such thatone junction cools while the other is heated. Reversal of the polarityof the voltage applied across the two junctions reverses the directionof the thermal gradient. Either the hot side or the cold side of thethermoelectric element faces radially inward in order to heat or cool,respectively, the target neural fibers that travel along the renalartery to achieve thermal renal neuromodulation. Optionally, theradially outward surface of the thermoelectric element may be insulatedto reduce a risk of thermal damage to the non-target tissues. The cuff1102 may comprise one or more temperature sensors, such asthermocouples, for monitoring the temperature of the target neuralfibers and/or of the non-target tissues.

FIG. 12 shows another method and apparatus 1200 utilizing the Peltiereffect. The apparatus 1200 comprises an implanted or external pump 1202connected to a renal artery cuff 1204 via inlet fluid conduit 1206 a andoutlet fluid conduit 1206 b. The inlet fluid conduit transfers fluidfrom the pump to the cuff, while the outlet fluid conduit transfersfluid from the cuff to the pump to circulate fluid through the cuff. Areservoir of fluid may be located in the cuff, the pump and/or in thefluid conduits.

The pump 1202 further comprises one or more thermoelectric or otherthermal elements in heat exchange contact with the fluid reservoir forcooling or heating the fluid that is transferred to the cuff tothermally modulate the target neural fibers. The apparatus 1200optionally may have controls for automatic or manual control of fluidheating or cooling, as well as fluid circulation within the cuff.Furthermore, the apparatus may comprise temperature and/or renalsympathetic neural activity monitoring or feedback control. Although theapparatus illustratively is shown unilaterally treating neural fibersinnervating a single kidney, it should be understood that bilateraltreatment of neural fibers innervating both kidneys alternatively may beprovided.

Thermal renal neuromodulation alternatively may be achieved via pulsedor continuous high-intensity focused ultrasound. High intensity focusedultrasound also may induce reversible or irreversible electroporation inthe target neural fibers. Furthermore, the ultrasound may be deliveredover a full 360° (e.g. when delivered intravascularly) or over a radialsegment of less than 360° (e.g., when delivered intravascularly,extravascularly, intra-to-extravascularly, or a combination thereof).FIGS. 13A and B illustrate an embodiment of an ultrasonic apparatus 1300comprising a catheter 1302, one or more ultrasound transducers 1304positioned along the shaft of the catheter, and an inflatable balloon1306 around the transducers 1304. The ultrasound transducers 1304 arecoupled to an ultrasound signal generator via conductors 1307. Theballoon 1306 can have an acoustically reflective portion 1308 forreflecting an ultrasound wave and an acoustically transmissive portion1309 the wave through which the ultrasonic energy can pass. In thismanner, the wave may be focused as shown at a focal point or radius Ppositioned a desired focal distance from the catheter shaft. In analternative embodiment, the transducers may be attached directly to theballoon.

The focal distance may be specified or dynamically variable such thatthe ultrasonic wave is focused at a desired depth on target neuralfibers outside of the vessel. For example, a family of catheter sizesmay be provided to allow for a range of specified focal distances. Adynamically variable focal distance may be achieved, for example, viacalibrated expansion of the balloon.

Focusing the ultrasound wave may produce a reverse thermal gradient thatprotects the non-target tissues and selectively affect the target neuralfibers to achieve thermal renal neuromodulation via heating. As aresult, the temperature at the vessel wall may be less than thetemperature at the target tissue. FIG. 13A shows the apparatus 1300 in areduced delivery and retrieval configuration, and FIG. 13B shows theapparatus 1300 in an expanded deployed configuration.

FIG. 14 shows an alternative embodiment of an ultrasonic 1400 having acatheter 1402, a conductor 1403, and concave ultrasound transducers1401. The concave ultrasound transducers 1404 direct the energy to aspecific focal point P. A such, the concave transducers 1404 areself-focusing and eliminate need of the reflective portion of theballoon 366 (e.g., the balloon may be acoustically transmissive at allpoints).

The apparatus described above with respect to FIGS. 3-14 optionally maybe used to quantify the efficacy, extent or cell selectivity ofthermally-induced renal neuromodulation in order to monitor and/orcontrol the neuromodulation. As discussed previously, the apparatus mayfurther comprise one or more sensors, such as thermocouples or imagingtransducers, for measuring and monitoring one or more parameters of (a)the apparatus, (b) target neural fibers and/or (c) non-target tissues.For example, a temperature rise or drop above or below certainthresholds is expected to thermally ablate, non-ablatively injure,freeze or otherwise damage the target neural fibers to thereby modulatethe target neural fibers.

FIGS. 15A and 15B classify the various types of thermal neuromodulationthat may be achieved with the apparatus and methods of the presentinvention. FIGS. 15A and 15B are provided only for the sake ofillustration and should in no way be construed as limiting. FIG. 15Aclassifies thermal neuromodulation due to heat exposure. As shown,exposure to heat in excess of a body temperature of about 37° C., butbelow a temperature of about 45° C., may induce thermal injury viamoderate heating of the target neural fibers or of vascular structuresthat perfuse the target fibers. For example, this may inducenon-ablative thermal injury in the fibers or structures. Exposure toheat above a temperature of about 45° C., or above about 60° C., mayinduce thermal injury via substantial heating of the fibers orstructures. For example, such higher temperatures may thermally ablatethe target neural fibers or the vascular structures. In some patients,it may be desirable to achieve temperatures that thermally ablate thetarget neural fibers or the vascular structures, but that are less thanabout 90° C., or less than about 85° C., or less than about 80° C.,and/or less than about 75° C. Regardless of the type of heat exposureutilized to induce the thermal neuromodulation, a reduction in renalsympathetic nerve activity (“RSNA”) is expected.

As seen in FIG. 15B, thermal cooling for neuromodulation includesnon-freezing thermal slowing of nerve conduction and/or nerve injury, aswell as freezing thermal nerve injury. Non-freezing thermal cooling mayinclude reducing the temperature of the target neural fibers or of thevascular structures that feed the fibers to temperatures below the bodytemperature of about 37° C., or below about 20° C., but above thefreezing temperature of about 0° C. This non-freezing thermal coolingmay either slow nerve conduction or may cause direct neural injury.Slowed nerve conduction may use continuous or intermittent cooling ofthe target neural fibers to sustain the desired thermal neuromodulation,while direct neural injury may require only a discrete treatment toachieve sustained thermal neuromodulation. Thermal cooling forneuromodulation also may include freezing thermal nerve injury byreducing the temperature of the target neural fibers or of the vascularstructures that feed the fibers to temperatures below the freezing pointof about 0° C. Regardless of the type of cold exposure utilized toinduce the thermal neuromodulation (freezing or non-freezing), areduction in renal sympathetic nerve activity (“RSNA”) is expected.

FIG. 16 shows one embodiment of an intravascular pulsed electric fieldapparatus 1600 in accordance with the present invention that includesone or more electrodes configured to physically contact a target regionwithin the renal vasculature and deliver a pulsed electric field acrossa wall of the vasculature. The apparatus 1600 is shown within apatient's renal artery RA, but it can be positioned in otherintravascular locations (e.g., the renal vein). This embodiment of theapparatus 1600 comprises an intravascular catheter 1610 having aproximal section 1611 a, a distal section 1611 b, and a plurality ofdistal electrodes 1612 at the distal section 1611 b. The proximalsection 1611 a generally has an electrical connector to couple thecatheter 1610 to a pulse generator, and the distal section 1611 b inthis embodiment has a helical configuration. The apparatus 1600 iselectrically coupled to a pulsed electric field generator 1600 locatedproximal and external to the patient; the electrodes 1612 areelectrically coupled to the generator via catheter 1610. The generator1600 may be utilized with any embodiment of the present inventiondescribed hereinafter for delivery of a PEF with desired fieldparameters. It should be understood that electrodes of embodimentsdescribed hereinafter may be connected to the generator, even if thegenerator is not explicitly shown or described with each variation.

The helical distal section 1611 b of catheter 1610 is configured tooppose the vessel wall and bring electrodes 1612 into close proximity toextra-vascular neural structures. The pitch of the helix can be variedto provide a longer treatment zone, or to minimize circumferentialoverlap of adjacent treatments zones in order to reduce a risk ofstenosis formation. This pitch change can be achieved by combining aplurality of catheters of different pitches to form catheter 1610, or byadjusting the pitch of catheter 1610 through the use of internal pullwires, adjusting mandrels inserted into the catheter, shaping sheathsplaced over the catheter, or by any other suitable means for changingthe pitch either in-situ or before introduction into the body.

The electrodes 1612 along the length of the pitch can be individualelectrodes, a common but segmented electrode, or a common and continuouselectrode. A common and continuous electrode may, for example, comprisea conductive coil formed into or placed over the helical portion ofcatheter 1610. A common but segmented electrode may, for example, beformed by providing a slotted tube fitted onto or into the helicalportion of the catheter, or by electrically connecting a series ofindividual electrodes.

Individual electrodes or groups of electrodes 1612 may be configured toprovide a bipolar signal, or all or a subset of the electrodes may beused together in conjunction with a separate external patient ground formonopolar use (the ground pad may, for example, be placed on thepatient's leg). Electrodes 1612 may be dynamically assignable tofacilitate monopolar and/or bipolar energy delivery between any of theelectrodes and/or between any of the electrodes and an external ground.

Catheter 1610 may be delivered to renal artery RA in a low profiledelivery configuration within sheath 1650. Once positioned within theartery, the catheter may self-expand or may be expanded actively, e.g.,via a pull wire or a balloon, into contact with an interior wall of theartery. A pulsed electric field then may be generated by the PEFgenerator 1600, transferred through catheter 1610 to electrodes 1612,and delivered via the electrodes 1612 across the wall of the artery. Inmany applications, the electrodes are arranged so that the pulsedelectric field is aligned with the longitudinal dimension of the arteryto modulate the neural activity along the renal nerves (e.g.,denervation). This may be achieved, for example, via irreversibleelectroporation, electrofusion and/or inducement of apoptosis in thenerve cells.

FIG. 17 illustrates an apparatus 1720 for neural modulation inaccordance with another embodiment of the invention. The apparatus 1720includes a pair of catheters 1722 a and 1722 b having expandable distalsections 1723 a and 1723 b with helical electrodes 1724 a and 1724 b,respectively. The helical electrodes 1724 a and 1724 b are spaced apartfrom each other by a desired distance within a patient's renalvasculature. Electrodes 1724 a-b may be actuated in a bipolar fashionsuch that one electrode is an active electrode and the other is a returnelectrode. The distance between the electrodes may be altered as desiredto change the field strength and/or the length of nerve segmentmodulated by the electrodes. The expandable helical electrodes maycomprise shape-memory properties that facilitate self-expansion, e.g.,after passage through sheath 1750, or the electrodes may be activelyexpanded into contact with the vessel wall, e.g., via an inflatableballoon or via pull wires, etc. The catheters 1722 a-b preferably areelectrically insulated in areas other than the distal helices ofelectrodes 1724 a-b.

It is expected that thermally-induced renal neuromodulation, whetherdelivered extravascularly, intravascularly, intra-to-extravascularly ora combination thereof, may alleviate clinical symptoms of CHF,hypertension, renal disease, myocardial infarction, atrial fibrillation,contrast nephropathy and/or other cardio-renal diseases for a period ofmonths, (potentially up to six months or more). This time period may besufficient to allow the body to heal; for example, this period mayreduce the risk of CHF onset after an acute myocardial infarction, tothereby alleviating a need for subsequent re-treatment. Alternatively,as symptoms reoccur, or at regularly scheduled intervals, the patientmay receive repeat therapy. Thermally-induced renal neuromodulation alsomay systemically reduce sympathetic tone.

FIG. 18 shows external renal nerve stimulator apparatus 1806 connectedto the electrode tip 1808 by the catheter 1801. A catheter is insertedvia an insertion site 1803 into the femoral vein 1805 into the vena cava1802 and further into the renal vein 1804. The tip 1808 is then broughtinto the electric contact with the wall of the vein 1804. Hooks orscrews, similar to ones used to secure pacemaker leads, can be used toanchor the tip and improve the electric contact. The tip 1808 can haveone, two or more electrodes integrated in its design. The purpose of theelectrodes is to generate the electric field sufficiently strong toinfluence traffic along the renal nerve 205 stimulating the kidney 208.

Two potential uses for the embodiment shown on FIG. 18 are the acuteshort-term stimulation of the renal nerve and the implanted embodiment.For short term treatment, a catheter equipped with electrodes on the tipis positioned in the renal vein. The proximal end of the catheter isleft outside of the body and connected to the electro stimulationapparatus. For the implanted application, the catheter is used toposition a stimulation lead, which is anchored in the vessel and left inplace after the catheter is withdrawn. The lead is then connected to theimplantable stimulator that is left in the body and the surgical site isclosed. Patients have the benefit of mobility and lower risk ofinfection with the implanted stimulator-lead system.

Similar to the venous embodiment, an arterial system can be used.Catheter will be introduced via the femoral artery and aorta (not shown)into the renal artery 1807. Arterial catheterization is more dangerousthan venous but may achieve superior result by placing stimulationelectrode (or electrodes) in close proximity to the renal nerve withoutsurgery.

Ablation of conductive tissue pathways is another commonly usedtechnique to control aterial or ventricular tachycardia of the heart.Ablation can be performed by introduction of a catheter into the venoussystem in close proximity of the sympathetic renal nerve subsequentablation of the tissue. Catheter based ablation devices were previouslyused to stop electric stimulation of nerves by heating nerve tissue withRF energy that can be delivered by a system of electrodes. RF energythus delivered stops the nerve conduction. U.S. Pat. No. 6,292,695describes in detail a method and apparatus for transvascular treatmentof tachycardia and fibrillation with nerve stimulation and ablation.Similar catheter based apparatus can be used to ablate the renal nervewith an intent to treat CRF. The method described in this invention isapplicable to irreversible ablation of the renal nerve by electricenergy, cold, or chemical agents such as phenol or alcohol.

Thermal means may be used to cool the renal nerve and adjacent tissue toreduce the sympathetic nerve stimulation of the kidney. Specifically,the renal nerve signals may be dampened by either directly cooling therenal nerve or the kidney, to reduce their sensitivity, metabolicactivity and function, or by cooling the surrounding tissue. An exampleof this approach is to use the cooling effect of the Peltier device.Specifically, the thermal transfer junction may be positioned adjacentthe vascular wall or a renal artery to provide a cooling effect. Thecooling effect may be used to dampen signals generated by the kidney.Another example of this approach is to use the fluid delivery device todeliver a cool or cold fluid (e.g. saline).

Referring to FIGS. 19A and 19B, variations of the invention comprisingdetectors or other elements for measuring or monitoring treatmentefficacy are described. Variations of the invention may be configured todeliver stimulation electric fields, in addition to denervating ormodulating PEFs. These stimulation fields may be utilized to properlyposition the apparatus for treatment and/or to monitor the effectivenessof treatment in modulating neural activity. This may be achieved bymonitoring the responses of physiologic parameters known to be affectedby stimulation of the renal nerves. Such parameters comprise, forexample, renin levels, sodium levels, renal blood flow and bloodpressure. Stimulation also may be used to challenge the denervation formonitoring of treatment efficacy: upon denervation of the renal nerves,the known physiologic responses to stimulation should no longer occur inresponse to such stimulation.

Efferent nerve stimulation waveforms may, for example, comprisefrequencies of about 1-10 Hz, while afferent nerve stimulation waveformsmay, for example, comprise frequencies of up to about 50 Hz. Waveformamplitudes may, for example, range up to about 50V, while pulsedurations may, for example, range up to about 20 milliseconds. When thenerve stimulation waveforms are delivered intravascularly, as in severalembodiments of the present invention, field parameters such asfrequency, amplitude and pulse duration may be modulated to facilitatepassage of the waveforms through the wall of the vessel for delivery totarget nerves. Furthermore, although exemplary parameters forstimulation waveforms have been described, it should be understood thatany alternative parameters may be utilized as desired.

The electrodes used to deliver PEFs in any of the previously describedvariations of the present invention also may be used to deliverstimulation waveforms to the renal vasculature. Alternatively, thevariations may comprise independent electrodes configured forstimulation. As another alternative, a separate stimulation apparatusmay be provided.

One way to use stimulation to identify renal nerves is to stimulate thenerves such that renal blood flow is affected—or would be affected ifthe renal nerves had not been denervated or modulated. Stimulation actsto reduce renal blood flow, and this response may be attenuated orabolished with denervation. Thus, stimulation prior to neural modulationwould be expected to reduce blood flow, while stimulation after neuralmodulation would not be expected to reduce blood flow to the same degreewhen utilizing similar stimulation parameters and location(s) as priorto neural modulation. This phenomenon may be utilized to quantify anextent of renal neuromodulation. Variations of the present invention maycomprise elements for monitoring renal blood flow or for monitoring anyof the other physiological parameters known to be affected by renalstimulation.

In FIG. 19A, an apparatus 1980 to achieve renal denervation including anelement for monitoring of renal blood flow is shown. Apparatus 1980comprises catheter 1982 having optional inflatable balloon or centeringelement 1984, shaft electrodes 1986 a and 286 b disposed along the shaftof the catheter on either side of the balloon, as well as optionalradiopaque markers 1988 disposed along the shaft of the catheter,illustratively in line with the balloon. Balloon 1984 serves as both acentering element for electrodes 1986 and as an electrical insulator fordirecting the electric field. Guidewire 1950 having Doppler ultrasoundsensor 1952 has been advanced through the lumen of catheter 1982 formonitoring blood flow within renal artery RA. Doppler ultrasound sensor1952 is configured to measure the velocity of flow through the artery. Aflow rate then may be calculated according to the formula:

Q=VA

where Q equals flow rate, V equals flow velocity and A equalscross-sectional area. A baseline of renal blood flow may be determinedvia measurements from sensor 1952 prior to delivery of a stimulationwaveform, then stimulation may be delivered between electrodes 1986,preferably with balloon 1984 deflated. Alteration of renal blood flowfrom the baseline, or lack thereof, may be monitored with sensor 1952 toidentify optimal locations for neuromodulation and/or denervation of therenal nerves.

FIG. 19B illustrates a variation of the apparatus of FIG. 19A, whereinDoppler ultrasound sensor 1952 is coupled to the shaft of catheter 1982.Sensor 1952 illustratively is disposed proximal of balloon 1984, but itshould be understood that the sensor alternatively may be disposeddistal of the balloon.

In addition or as an alternative to intravascular monitoring of renalblood flow via Doppler ultrasound, such monitoring optionally may beperformed from external to the patient whereby renal blood flow isvisualized through the skin (e.g., using an ultrasound transducer). Inanother variation, one or more intravascular pressure transducers may beused to sense local changes in pressure that may be indicative of renalblood flow. As yet another alternative, blood velocity may bedetermined, for example, via thermodilution by measuring the time lagfor an intravascular temperature input to travel between points of knownseparation distance.

For example, a thermocouple may be incorporated into, or provided inproximity to, each electrode 1986, and chilled (i.e., lower than bodytemperature) fluid or saline may be infused proximally of thethermocouple(s). A time lag for the temperature decrease to registerbetween the thermocouple(s) may be used to quantify flowcharacteristic(s). A baseline estimate of the flow characteristic(s) ofinterest may be determined prior to stimulation of the renal nerves andmay be compared with a second estimate of the characteristic(s)determined after stimulation.

Commercially available devices optionally may be utilized to monitortreatment. Such devices include, for example, the SmartWire™, FloWire™and WaveWire™ devices available from Volcano™ Therapeutics Inc., ofRancho Cordova, Calif., as well as the PressureWire® device availablefrom RADI Medical Systems AB of Uppsala, Sweden. Additional commerciallyavailable devices will be apparent. An extent of electroporationadditionally or alternatively may be monitored directly using ElectricalImpedance Tomography (“EIT”) or other electrical impedance measurements,such as an electrical impedance index.

Although preferred illustrative variations of the present invention aredescribed above, it will be apparent to those skilled in the art thatvarious changes and modifications may be made thereto without departingfrom the invention. It is intended in the appended claims to cover allsuch changes and modifications that fall within the true spirit andscope of the invention.

1. A method for thermally-induced renal neuromodulation, the methodcomprising: positioning a thermal apparatus at least proximate to aneural fiber that contributes to renal function; and delivering pulsedenergy via the thermal apparatus to modulate a function of the neuralfiber via thermal effects.
 2. The method of claim 1, wherein positioningthe thermal apparatus further comprises delivering the device via anapproach chosen from the group consisting of intravascularly,extravascularly, intra-to-extravascularly and combinations thereof. 3.The method of claim 1, wherein delivering the pulsed energy furthercomprises directly applying pulsed thermal energy to the neural fiber.4. The method of claim 1, wherein delivering the pulsed energy furthercomprises indirectly applying pulsed thermal energy to the neural fiber.5. The method of claim 1, wherein delivering the pulsed energy furthercomprises delivering a pulsed thermal electric field to the neural fibervia at least one electrode.
 6. The method of claim 5, whereinpositioning the thermal apparatus further comprises intravascularlydelivering the device, and wherein delivering a pulsed thermal electricfield to the neural fiber via at least one electrode further comprisesdelivering the pulsed thermal electric field via at least onewall-contact electrode.
 7. The method of claim 1 further comprisingmonitoring a parameter of at least one of the neural fiber, a non-targettissue or the apparatus during thermally-induced modulation of thefunction of the neural fiber.
 8. The method of claim 7 furthercomprising controlling the delivery of the pulsed energy in response tothe monitored parameter.
 9. The method of claim 1 further comprisingactively protecting non-target tissue during thermal modulation of theneural fiber.
 10. The method of claim 9, wherein actively protecting thenon-target tissue further comprises reducing a degree of thermal damageinduced in the non-target tissue.
 11. The method of claim 9, whereinactively protecting the non-target tissue further comprises delivering athermal fluid to a vicinity of the non-target tissue.
 12. The method ofclaim 9, wherein actively protecting the non-target tissue furthercomprises establishing a heat transfer rate discrepancy between thenon-target tissue and the neural fiber.
 13. The method of claim 1,wherein delivering the pulsed energy further comprises delivering pulsedhigh intensity focused ultrasound to the neural fiber.
 14. The method ofclaim 1, wherein delivering the pulsed energy further comprises heatingthe neural fiber via the pulsed thermal energy.
 15. The method of claim1, wherein delivering the pulsed energy further comprises cooling theneural fiber via the pulsed thermal energy.
 16. Apparatus forthermally-induced renal neuromodulation, the apparatus comprising: apulse generator; a device configured for delivery within a blood vesselto a vicinity of a neural fiber that contributes to renal function; anda thermal modulation element supported by the device, the thermalmodulation element being configured to expand from a first dimension toa second dimension, wherein the thermal modulation element is configuredto (a) contact a wall of the blood vessel upon expansion of the thermalmodulation element to the second dimension within the blood vessel, and(b) transmit pulsed thermal energy relative to the neural fiber tothermally induce modulation of a function of the neural fiber uponexpansion of the thermal modulation element to the second dimensionwithin the blood vessel.
 17. The apparatus of claim 16, wherein thethermal modulation element is configured to self-expand from the firstdimension to the second dimension.
 18. The apparatus of claim 16,wherein the device further comprises an expandable member that is atleast proximate to the thermal modulation element, the expandable memberbeing configured to expand the thermal modulation element from the firstdimension to the second dimension.
 19. The apparatus of claim 16,wherein the thermal modulation element is configured for directapplication of the pulsed thermal energy relative to the neural fiber.20. The apparatus of claim 16, wherein the thermal modulation element isconfigured for indirect application of the pulsed thermal energyrelative to the neural fiber.
 21. The apparatus of claim 16, wherein thethermal modulation element further comprises at least one electrodeconfigured to deliver a pulsed thermal electric field relative to theneural fiber.
 22. The apparatus of claim 16, wherein the apparatusfurther comprises at least one sensor.
 23. The apparatus of claim 22,wherein the sensor is configured to monitor a physiological parameter ofthe neural fiber.
 24. The apparatus of claim 22, wherein the sensor isconfigured to monitor a physiological parameter of non-target tissue.25. The apparatus of claim 22, wherein the sensor is configured tomonitor a parameter of the apparatus.
 26. The apparatus of claim 22further comprising a feedback control in communication with the sensor.27. The apparatus of claim 16, wherein the apparatus further comprises aprotective element configured to reduce a degree of thermal damageinduced in non-target tissue.
 28. The apparatus of claim 16, wherein thethermal modulation element further comprises at least one thermoelectricelement configured to deliver the pulsed thermal energy relative to theneural fiber.
 29. The apparatus of claim 16, wherein the thermalmodulation element further comprises a high intensity focused ultrasoundelement.
 30. The apparatus of claim 16, wherein the thermal modulationelement further comprises a thermal fluid.
 31. The apparatus of claim27, wherein the protective element comprises an infusion elementconfigured to infuse a thermal fluid in a vicinity of the non-targettissue.
 32. The apparatus of claim 16 further comprising an occlusionelement configured to temporarily occlude blood flow within the bloodvessel.